Abstract 3853: The TWIST1-p27 signaling pathway is a critical determinant of MET TKI cell cycle arrest and resistance in <i>MET</i> altered non-small cell lung cancer
Authors: Vinod Kumar, Zachary A. Yochum, Princey Devadassan, Eric Huang, Ethan Miller, Vasavi Ayyala, Purva H. Rumde, Roja Baruwal, James O’Brien, Laura P. Stabile, Timothy F. Burns
Journal: Cancer Research (2023)

Abstract Advancement in classifying NSCLC into molecularly defined subgroup that respond to specific therapies have shifted the treatment paradigm towards personalized targeted therapy approach. A major obstacle for the treatment of oncogene driven non-small cell lung cancer (NSCLC) patients is both de novo and acquired resistance to targeted therapies. Approximately 4-6% of NSCLC patients harbor MET amplifications/mutations which are important targetable oncogenic drivers in the clinic. In addition, MET amplification has also emerged as a common mechanism of acquired resistance to EGFR TKIs as well as other targeted therapies. Crizotinib, tepotinib and capmatinib are FDA approved MET TKIs for MET exon 14 skipping mutant NSCLC and have shown activity against MET amplified NSCLC as well. Despite high response rates with these newer TKIs, the majority of patients with targetable MET alterations fail to respond and acquired resistance is inevitable. Multiple molecular mechanisms of MET TKIs resistance encompassing both on-target (HGF overexpression) and bypass have been identified. Furthermore, at the time of resistance, an epithelial-to-mesenchymal (EMT) phenotype is often observed. We have found that HGF/MET pathway is a major regulator of the TWIST1, TWIST1 is required for MET altered NSCLC and cooperatives with HGF in vivo during tumorigenesis. Here, we reported that EMT transcription factor TWIST1 mediates a bypass of a MET TKI-mediated p27-dependent growth arrest. To study the mechanism of TKI resistance in MET altered NSCLC, we used multiple MET dysregulated human cell lines (H1437, H596, H1993, and H1648), a novel acquired resistance model of MET TKI resistance (H1993-CR cells), two syngeneic tobacco carcinogen induced mouse lung cell lines (FVBW-17 and FVBCH-17), and three different animal models (mouse xenografts, PDXs, transgenic animals). We found that TWIST1 overexpression led to MET TKI resistance in vitro and in vivo in MET altered cell lines by overcoming cell cycle arrest. This was accompanied by a failure to induce p27 in the presence of TWIST1 overexpression. Similarly, loss of p27 induction and G1 arrest was also observed in our model of acquired MET TKI resistance. Conversely, TWIST1 inhibition restore sensitivity to TKIs in vitro and in vivo and lead to induction of p27. p27 appears to be require for MET TKI induced cell cycle arrest and sensitivity as silencing p27 lead to MET TKI resistance. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome HGF-MET-driven resistance in MET-driven NSCLC. Citation Format: Vinod Kumar, Zachary A. Yochum, Princey Devadassan, Eric Huang, Ethan Miller, Vasavi Ayyala, Purva H. Rumde, Roja Baruwal, James O’Brien, Laura P. Stabile, Timothy F. Burns. The TWIST1-p27 signaling pathway is a critical determinant of MET TKI cell cycle arrest and resistance in MET altered non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3853.